Abstract
Hyperammonemia in neonates and infants affects brain development and causes mental retardation. We report that ammonium impaired cholinergic axonal growth and altered localization and phosphorylation of intermediate neurofilament protein in rat reaggregated brain cell primary cultures. This effect was restricted to the phase of early maturation but did not occur after synaptogenesis. Exposure to NH4Cl decreased intracellular creatine, phosphocreatine, and ADP. We demonstrate that creatine cotreatment protected axons from ammonium toxic effects, although this did not restore high-energy phosphates. The protection by creatine was glial cell-dependent. Our findings suggest that the means to efficiently sustain CNS creatine concentration in hyperammonemic neonates and infants should be assessed to prevent impairment of axonogenesis and irreversible brain damage.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Diphosphate / metabolism
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Adenosine Monophosphate / metabolism
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Adenosine Triphosphate / metabolism
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Ammonium Chloride / toxicity*
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Animals
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Axons / drug effects
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Axons / metabolism
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Axons / physiology
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Cell Differentiation / physiology
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Cell Division / drug effects
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Cells, Cultured
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Choline O-Acetyltransferase / biosynthesis
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Coculture Techniques
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Creatine / metabolism
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Creatine / pharmacology*
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Dose-Response Relationship, Drug
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GAP-43 Protein / biosynthesis
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Glucose / pharmacokinetics
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Immunohistochemistry
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Intracellular Fluid / metabolism
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Lactic Acid / metabolism
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Neurofilament Proteins / biosynthesis
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Neuroglia / cytology
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Neuroglia / metabolism*
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Neurons / cytology
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Neurons / drug effects*
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Neurons / metabolism
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Phosphocreatine / metabolism
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Quaternary Ammonium Compounds / pharmacokinetics
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Rats
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Telencephalon / cytology
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Telencephalon / embryology
Substances
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GAP-43 Protein
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Neurofilament Proteins
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Quaternary Ammonium Compounds
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Ammonium Chloride
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Phosphocreatine
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neurofilament protein M
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Lactic Acid
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Adenosine Monophosphate
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Adenosine Diphosphate
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Adenosine Triphosphate
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Choline O-Acetyltransferase
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Glucose
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Creatine